SYNTHESES OF LABELED HEMES FOR PROTEIN NMR STUDIES

用于蛋白质 NMR 研究的标记血红素的合成

• 批准号: 2215552
• 负责人: Kevin M Smith
• 金额: $ 21.26万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-04-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2215552
• 关键词: Diels Alder reaction; Raman spectrometry; adduct; carbon; catalase; chemical synthesis; circular dichroism; cytochromes; deuterium; dimer; heme; hemoglobin; hemoprotein; hemoprotein structure; metalloproteins; myoglobin; nuclear magnetic resonance spectroscopy; photosensitizing agents; porphyrins; protein structure function; radiopharmacology; radiotracer; stable isotope

The objective of this proposal is discovery of fundamental chemistry and synthetic methodology for obtaining porphyrin systems of biological interest, with special emphasis on development of methodology for isotope labeling of hemes so as to provide access to unique spectroscopic probes of structure- activity relationships in heme proteins. Methodology will be developed which will permit synthesis of natural hemes regioselectively labeled in predetermined positions with deuterium, carbon-13, and nitrogen- 15, if sufficient is available, compounds resulting from these studies will subsequently be used for NMR, circular dichroism, and resonance Raman studies to gain an understanding of heme apoprotein interactions and structure/function relationships in a variety of biologically important heme proteins such as hemoglobins, myoglobins, cytochromes, oxygenases, and peroxidases. It is also proposed to synthesize a variety of meso- methylated hemes (for heme oxygenase studies), unlabeled heme analogues, heme dimers, and hydrohemes, as well as hemes with interrupted conjugation, isoporphyrin systems, and non-planar porphyrins of various types. We shall continue studies of reduced porphyrin systems known as porphodimethenes and shall further develop very simple, as well as more complex, methodology for obtaining porphyrin systems. Thr proposed work will provide a synthetic backbone and anchor point for spectroscopic methodology being developed to advance the understanding heme protein function, and of structural and electronic factors which cause several debilitating diseases such as anemias. Two fundamental approaches for synthesis of novel compounds will be developed; carbon-13, nitrogen-15, unlabeled porphyrins, and meso- methylporphyrins will be obtained by total synthesis from acyclic precursors. Some methods for such approaches have already been worked out, but improvements and discovery of new methodology, simple and multistep, is planned and anticipated. Some deuterium labeled, carbon-13 labeled porphyrins, protoporphyrin IX analogues, N-methyl- land meso- methylporphyrins and other hemes will be approached by manipulation of substituents on existing natural commercially available porphyrins.

该提案的目标是发现基础化学和 获得生物卟啉系统的合成方法 兴趣，特别强调同位素方法的开发 血红素标记，以便获得独特的光谱探针 血红素蛋白的结构-活性关系。 方法论将是 开发出能够区域选择性合成天然血红素的技术 在预定位置用氘、碳 13 和氮标记 15，如果有足够的可用，这些研究产生的化合物将 随后可用于 NMR、圆二色性和共振拉曼 研究以了解血红素脱辅基蛋白相互作用和 各种具有重要生物学意义的结构/功能关系 血红素蛋白，如血红蛋白、肌红蛋白、细胞色素、氧酶和 过氧化物酶。 还建议合成多种介观 甲基化血红素（用于血红素加氧酶研究）、未标记的血红素类似物、 血红素二聚体和水血红素，以及缀合中断的血红素， 异卟啉系统和各种类型的非平面卟啉。我们将 继续研究被称为卟啉二亚甲基的还原卟啉系统和 将进一步开发非常简单以及更复杂的方法 获得卟啉系统。 拟议的工作将提供一个综合的 正在开发的光谱方法的骨干和锚点 促进对血红素蛋白功能、结构和结构的理解 导致多种衰弱性疾病的电子因素，例如 贫血。 合成新化合物的两种基本方法将 被开发；碳 13、氮 15、未标记的卟啉和内消旋 由无环化合物全合成得到甲基卟啉 前体。 此类方法的一些方法已经制定出来， 但新方法的改进和发现，简单且多步骤，是 计划和预期的。 一些氘标记，碳13标记 卟啉、原卟啉 IX 类似物、N-甲基-和介观- 甲基卟啉和其他血红素将通过操纵来接近 现有市售天然卟啉上的取代基。